The invention concerns medicine, in particular the pharmaceutical industry, namely the production of compounds that influence metabolic processes in the human body, in particular oxygenation processes.
Common to neurodegenerative diseases is progressive loss of specific nerve cells, which are associated with protein aggregation, which is caused by oxidative stress. Oxidative stress is responsible for dysfunction or death of neurons, which is the important if not the main element of the pathogenesis of the disease.
Oxidative stress is a result of unregulated formation of active oxygen forms (AOF) or reactive oxygen species (ROS) such as hydrogen peroxide, superoxide anion radical, highly active hydroxyl radical, or peroxynitrite. A high level of oxygen absorption and low antioxidant status together with insufficient ability of the organism to regenerate tissues create an elevated level of sensitivity to oxidative damage.
Peroxidation of lipids is a result of attack of radical forms of active oxygen at the double bonds of unsaturated fatty acids such as linolenic and arachidonic acids. This leads to generation of active peroxy radicals, which initiate chain reactions that include further attack at the C═C bonds of unsaturated fatty acids. Decomposition products such as 4-hydroxy-2,3-nonenal, acrolein and malondialdehyde form as a result.
An increased level of 4-hydroxy-2,3-nonenal was found in the brains of Alzheimer's patients and patients with Parkinson disease. Increased levels of acrolein and malondialdehyde derivatives were detected in the brains of Alzheimer's patients. In Parkinson's there was an increase in the level of malondialdehyde. All four DNA bases are sensitive to oxidative damage including hydroxylation, formation of carbonyl groups and nitration (changes found in the brain DNA of Alzheimer's patients.)
Increased levels of 8-hydroxyguanine and 8-hydroxy-2-deoxygyanosine (as a result of attack of hydroxyl radicals) are typical in the brains of Parkinson's patients.
Cells have their own defense mechanisms against oxidative stress, and changes seen in their activity are also good markers for oxidative stress. In the brains of patients with verified Alzheimer's disease, the activity of antioxidant proteins such as catalase, superoxide dismutase (SOD), glutathione peroxidase and glutathione reductase is increased. Oxidation of fatty acids mainly takes place in the mitochondria, and other cell compartments also contain enzymes capable of converting fatty acids to acetyl-SCoA by a pathway that is similar (but not identical) to what happens in mitochondria.
Oxidative stress (i.e., oxidation of lipids, proteins and DNA) causes damage to cell functions and formation of toxic compounds, such as peroxides, alcohols, aldehydes, ketones, cholesterol oxide. The last is toxic to lymphocytes and macrophages of blood vessels. Acrolein interrupts the reverse capture of glucose and glutamate from cell cultures, while 4-hydroxy-2,3-nonenal inhibits the neural glucose transporter, as well as the glutamate and Na+/K+-ATPase transporters. Modification of protein leads to damage to enzymes such as glutamate synthase and SOD, and oxidation of DNA lead to mutations. Disruption of intracellular calcium signaling/ROS-induced release of calcium leads to activation of glutamate receptors and, if there are other disruptions, it leads to activation of the apoptotic cascade, thus to programmed cell death.